Localized therapy delivery and local organ protection

ABSTRACT

A system for perfusing a localized site within a body includes a catheter assembly having a venous access line that is adapted to deliver perfusate to the localized site, a venous or arterial drainage line adapted to drain perfusate from the localized site, and an occlusion device adapted to prevent some or substantially all physiological blood flow between the localized site and the systemic circulation of the body during and in the course of perfusing and draining perfusate to and from the localized site. The system may include a blood circuit associated with the catheter assembly to facilitate blood conditioning for use as the perfusate, in the course of a controlled perfusion and/or drainage of untreated, treated, or inactivated treated blood to and from the localized site. A delivery machine may control the blood circuit and catheter assembly in order to both deliver perfusate to, and drain some or all perfusate from, the localized site in a manner that provides perfusate to substantially only the localized site.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/216,625, filed on Mar. 17, 2014, which itself claims priority to U.S.Provisional Patent Application Ser. No. 61/800,248, filed on Mar. 15,2013 and entitled “Advancement of Localized Therapy Delivery and LocalOrgan Protection”, and further claims priority to and is acontinuation-in-part of U.S. patent application Ser. No. 13/576,302,filed on Jul. 31, 2012 and entitled “Localized Therapy Delivery andLocal Organ Protection”, itself a United States national phaseapplication under 35 U.S.C. § 371 of International Application SerialNo. PCT/US11/23471, filed on Feb. 2, 2011 and entitled “LocalizedTherapy Delivery and Local Organ Protection”, which claims priority toU.S. Provisional Application Ser. No. 61/300,703, filed on Feb. 2, 2010,the contents of each of which being incorporated herein in theirentirety.

FIELD OF THE INVENTION

The present invention relates to therapy delivery generally, and moreparticularly to localized delivery of therapy to target body tissuestructures, wherein the therapy may be contained at a localized site tominimize or eliminate systemic effect of the therapy.

BACKGROUND OF THE INVENTION

Therapy administration techniques have long relied upon systemicpathways due to the ease of accessibility of such pathways. For example,systemic pathways may be accessed through oral, intravenous,intramuscular, per-cutaneous, sub-dermal, and inhalation deliverytechniques. However, most therapies target a specific tissue structure,wherein systemic administrations for such local treatment may beinefficient or ineffective as a result of dilution of the systemicadministration and/or undesirable systemic side effects. In either case,maximum benefit of the treatment is not likely realized through systemicadministration.

Currently practiced localized administration techniques improve theeffectiveness of local treatment by direct application to the targettissue structure. However, dilution of the administered treatment stilloccurs as a result of systemic blood circulation through the tissuestructure. Moreover, convective transport of the applied treatment mayalso lead to systemic side effects which limit the potential treatmentpotency, even when administered locally. Consequently, prolongedapplication of localized, but non-isolated therapy administration doesnot typically maintain the high organ-to-body concentration gradientneeded to provide the maximal effectiveness of the therapy.

Many treatments that show promising results in animal research fail totranslate to clinical uses due to intolerable systemic and/or localadverse effects outside the tissue structure targeted for treatment.Such therapies may be aggressive, but crucial treatments for severe orlife-threatening conditions. One example is the treatment of a solidtumor, which is typically approached through a systemic intravenousinfusion of chemotherapeutic agents to reach the tumor site. Systemictoxicity of many chemotherapeutic agents, however, restricts the abilityto maintain a dose rate and/or duration of exposure to effect aresponse.

Another example is the treatment of ischemic tissue caused by an acutesevere disruption in arterial circulation to the damaged tissue.Examples of ischemic injuries are myocardial infarction (heart attack)and cerebrovascular accident (stroke). Treatment of ischemic injury hastypically involved a direct arterial intervention. However, conventionalarterial intervention techniques require significant time to complete,and introduce risk of secondary injury, such as through arterial emboliand reperfusion injury, which may be caused by a sudden return of bloodsupply to the tissue after the arterial disruption is resolved.

The current standard treatment for heart attack is reperfusion therapy,primarily by percutaneous coronary intervention (PCI), such as stentand/or balloon angioplasty and/or thrombolytic therapy. The goal of suchtreatment is to reestablish the tissue perfusion to the myocardium asearly as possible in order to minimize tissue damage, and to promotetissue salvage. PCI, however, can cause clot debris to flow downstreamand result in a distal occlusion of smaller arteries. Moreover, thereturn of blood supply to ischemic tissue itself may attack the tissue(i.e. reperfusion injury).

The concept of tissue cooling treatment to prevent or minimize tissuedamage caused by arterial circulation disruption and/or reperfusioninjury has been explored. However, conventional total-body cooling cancause systemic adverse effects, such as severe shivering, hemodynamicinstability due to electrolyte shift and systemic vascular dilation,coagulopathy or increased bleed tendency, and infection, which furthercomplicates patient management. In addition, conventional therapeutichypothermia administrations may result in ineffective therapy deliveryto the target tissue, and is unable to rapidly cool the target issuewithout the undesired systemic side effects described above. Thedrawbacks of conventional total-body cooling therefore generallyprohibits clinical use of the cooling treatment in both severe ischemicand traumatic injuries, despite evidence in preclinical researchdemonstrating the effective reduction of tissue death after severeinjury with the cooling treatment.

Retrograde therapeutic perfusion, such as perfusion of oxygenated blooddelivered retrogradedly to the endangered ischemic myocardium, has beenexplored as a stand-alone or adjunctive treatment to PCI to causeoxygenated blood to rapidly reach an underperfused myocardium tissue.Retroperfusion of oxygenated blood has also been explored in the contextof ischemic brain stroke, in which autologous oxygenated blood may bepumped into one or both of the cerebral venous sinuses through thejugular veins. One conventional method describes occluding both jugularveins by balloon catheters or, alternatively, occluding the drainagepaths from higher up in the brain if desired, and continuously pumpingarterial blood into one or both of the cerebral sinuses.

In addition to rapidly providing oxygenated blood to ischemic tissue,researchers have realized that venous retroperfusion may provide anadvantageous technique for therapeutic hypothermia of retroperfusedtissue. Mild hypothermia (32-33° C.) with reperfusion therapy has beenshown to provide a significant improvement of tissue protection whencompared to reperfusion therapy alone. By directly treating tissuestructures with therapeutic cooling, many undesirable side effects ofsystem therapeutic cooling may be avoided.

Despite the promising outcomes of retroperfusion of oxygenated blood,and targeted therapeutic hypothermia through a retroperfusion platform,proposals to date have involved complex systems, including the need forarterial catheterization, and/or inadequate or problematicretroperfusion. Moreover, systems proposed to date fail to substantiallyisolate the target tissue structure, such that conventional therapydelivery typically results in contamination to the systemic circulation.For various applications, including therapeutic hypothermia, significantcontamination is undesired, and limits the effectiveness of the therapyon the targeted tissue structure.

It is therefore an object of the invention to deliver therapy locally,and to isolate the therapy substantially only to the target tissuestructure.

It is another object of the invention to maintain a high organ to bodytherapy gradient, wherein such gradient is the difference between thetherapeutic concentration at the target organ versus such therapeuticconcentration in the systemic circulation.

SUMMARY OF THE INVENTION

By means of the present invention, organ circulation may be isolatedfrom the systemic circulation so that the organ circulation iscompartmentalized from the systemic circulation, while still performingits function for the body. Therapy may therefore be delivered in amanner to maintain either a high organ-to-systemic or systemic-to-organtherapeutic gradient for an extended period of time. In a particularapplication, the present invention facilitates localized treatment of aspecific organ to prevent or minimize systemic side effects. Aggressivetreatments that are currently limited or impractical due to thepatient's ability to tolerate systemic side effects may potentially beapplied through the system of the present invention. Examples of suchaggressive treatments include therapeutic hypothermia and chemotherapy.On the other hand, when systemic treatment is preferred, but limited byits toxicity to vital organs, the organ circulatory isolation concept ofthe present invention may be used to prevent or minimize organ damagefrom the systemic treatment. Therefore, the ability to localize orisolate aggressive treatments to or from specific organs (tissuestructures) can expand the use of certain existing treatments to providemore benefits to more patients.

While several techniques and device configurations are proposed herein,the present concept may be generally described by: (i) localized therapydelivery, (ii) therapy isolation, and (iii) compartmental therapydeactivation. Such principles may be accomplished through acatheterization having an organ perfusion line, an organ drainage line,and a systemic line. As a result, a single catheter platform may serve avariety of clinical applications. In many situations, catheterizationwith the present system may involve relatively low-risk venous access,and does not require arterial intervention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram of a therapy delivery system of thepresent invention;

FIG. 2 is a schematic illustration of the system depicted in FIG. 1;

FIG. 3 is a schematic diagram of a therapy delivery system of thepresent invention;

FIG. 4 is a schematic illustration of the system depicted in FIG. 3;

FIG. 5 is a schematic illustration of the system depicted in FIG. 3;

FIG. 6 is a schematic diagram of a therapy delivery system of thepresent invention;

FIG. 7 is a schematic illustration of the system depicted in FIG. 6;

FIG. 8 is a schematic illustration of the system depicted in FIG. 6;

FIG. 9 is a schematic illustration of the system depicted in FIG. 6;

FIG. 10 is a schematic illustration of the system depicted in FIG. 6;

FIG. 11A is a schematic illustration of a therapy delivery system of thepresent invention;

FIG. 11B is a schematic illustration of a therapy delivery system of thepresent invention;

FIG. 12 is a schematic illustration of a therapy delivery system of thepresent invention;

FIG. 13A is an illustration of a balloon fixation device usable inconnection with the therapy delivery system of the present invention;

FIG. 13B is an illustration of a balloon fixation device usable inconnection with the therapy delivery system of the present invention;

FIG. 14 is a schematic diagram of a therapy delivery system of thepresent invention;

FIG. 15 is a schematic diagram of a portion of the system illustrated inFIG. 14;

FIG. 16 is a schematic diagram of a portion of the system illustrated inFIG. 14;

FIG. 17 is a schematic diagram of a portion of the system illustrated inFIG. 14;

FIG. 18 is a schematic illustration of an implementation of the therapydelivery system of the present invention;

FIG. 19A is a schematic illustration of a portion of the systemillustrated in FIG. 18;

FIG. 19B is a schematic illustration of a portion of the systemillustrated in FIG. 18;

FIG. 20A is a schematic illustration of a portion of the systemillustrated in FIG. 18;

FIG. 20B is a schematic illustration of a portion of the systemillustrated in FIG. 18;

FIG. 20C is a schematic illustration of a portion of the systemillustrated in FIG. 18;

FIG. 21 is a schematic flow diagram of a portion of the therapy deliverysystem of the present invention;

FIG. 22 is a schematic flow diagram of a portion of the therapy deliverysystem of the present invention;

FIG. 23 is a schematic flow diagram of a portion of the therapy deliverysystem of the present invention;

FIG. 24 is a schematic flow diagram of a portion of the therapy deliverysystem of the present invention;

FIG. 25 is a schematic flow diagram of a portion of the therapy deliverysystem of the present invention;

FIG. 26 is a schematic diagram of a therapy delivery system of thepresent invention;

FIG. 27 is a schematic diagram of a therapy delivery system of thepresent invention;

FIG. 28 is a schematic flow diagram of a therapy delivery system of thepresent invention; and

FIG. 29 is an annotated electrocardiogram signal.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The objects and advantages enumerated above, together with otherobjects, features, and advances represented by the present inventionwill now be presented in terms of detailed embodiments described withreference to the attached drawing figures which are intended to berepresentative of various possible configurations of the invention.Other embodiments and aspects of the invention are recognized as beingwithin the grasp of those having ordinary skill in the art.

An aspect of the present invention is the establishment of a tissuestructure circulatory compartment that is at least partially isolatedfrom the systemic circulation of the body. For the purposes of thepresent invention, the term “tissue structure” may mean a cell structureof a mammalian body, such as an organ or limb having blood circulationtherethrough. The terms “organ” and “tissue structure” may therefore beused interchangeably herein to refer to a cell structure of or in amammalian body through which sanguinous fluid is circulated. For thepurposes of the present invention, the term “systemic” may mean theoverall blood circulation of the mammalian body. An aspect of thepresent invention, therefore, is to at least partially separate bloodcirculation of a tissue structure from the remainder of the systemiccirculation. By at least partially isolating the tissue structurecirculation, localized tissue structure therapy and/or tissue structureprotection may be realized.

The present invention may be directed to delivering therapy through thevenous system of the target tissue structure to maximize the effects oflocalized treatment, and to at least partially isolate the tissuestructure circulation from the systemic circulation to minimize orprevent therapy dilution and/or systemic side effects. The venous systemprovides a relatively safe and direct access to a tissue structure andits capillary bed, without the risks associated with access to thearterial system. The approach of the present invention may be used invarious applications, including tissue structure-localized therapeutichypothermia, drug delivery, chemotherapy, and cell-based therapy.Moreover, the present invention may be employed to protect vulnerabletissue structures from systemic treatments, such as renal failure fromsystemic chemotherapy. A still further application of the presentinvention is local organ plasma paresis or organ dialysis for largeorgans with severe injury that could cause secondary systemic injury.

In some embodiments, therapy deactivation may be beneficial inminimizing or eliminating systemic impact of the delivered therapy.Therapy deactivation may include, for example, warming cooled blood tophysiologic temperature, metabolizing bioactive agents to minimize oreliminate toxins in the bioactive agents, and adding compensatory agentsto neutralize systemic activity of bioactive agents employed in thetherapy.

In one aspect of the present invention, circulation of a tissuestructure may be substantially completely isolated from the systemiccirculation. A schematic diagram of a complete tissue structureisolation arrangement is shown in FIG. 1, in which catheters may beinserted into an arterial inflow structure and a venous drainagestructure of a target tissue structure (organ). The catheters eachinclude an occlusion device that is adapted to selectively substantiallyocclude the respective arterial inflow structure or venous drainagestructure to thereby substantially occlude all arterial or venous flowtherethrough. Once placement of the catheters and respective occlusiondevices are deployed to complete the circulatory isolation of the targettissue structure, an extracorporeal blood conditioning apparatus isprovided to provide local blood circulation to the target tissuestructure.

The schematically illustrated complete isolation system 8 includes avenous catheter 10 having a distal portion 12 positionable at a venousdrainage structure 20 of the target tissue structure 11. Distal portion12 of venous catheter 10 includes a first occlusion device 14 that isadapted to selectively substantially occlude venous drainage structure20, and to thereby substantially occlude all venous drainage of tissuestructure 11.

As illustrated in FIG. 1, the flow direction of the circulation may beantegrade (artery to vein) or retrograde (vein to artery). Inembodiments employing retrograde flow and complete tissue structureisolation, the arterial circulation may be used as the drainage of theorgan (tissue structure) circulatory compartment. Retrograde flowthrough the organ circulatory compartment may be somewhat preferred overantegrade flow, in that venous systems typically have more collateralcirculation than do arterial systems. As a result, retrograde flow mayprovide more access to the organ tissues and its capillary bed thanantegrade flow. Moreover, retrograde perfusion may have better access toa post-occlusion ischemic area of the target organ (tissue structure).Retrograde flow may additionally minimize arterial damage and thepotential for debris occlusion through arterial embolism, as compared toantegrade flow through the organ circulatory compartment. Because theorgan circulation is controlled independently from the systemiccirculation, flow rate and pressure of perfusion of the organ may beindependently optimized to achieve maximum tissue perfusion or therapyexchange at the cellular level. Bi-directional flow through the organcirculatory compartment (alternating between antegrade and retrogradeflow) may also be beneficial to minimize vessel occlusion for prolongeduses of the therapy delivery of the present invention.

A blood conditioning apparatus within an extracorporeal blood loop isprovided in the system of the present invention to condition autologousblood for perfusion through the organ circulatory compartment. The bloodconditioning apparatus for extracorporeal therapy delivery may include aflow-volume adjusting mechanism to regulate or equate input and outputblood volumes to the organ circulatory compartment. The flow-volumeadjusting mechanism monitors input/output balance, and is adapted toselectively add or remove blood to or from the organ circulation loop,with the balancing blood sourced from the systemic circulation. In thismanner, the flow-volume adjusting mechanism is adapted to balance theinput/output flow through the target organ.

In some embodiments, the blood conditioning apparatus is further adaptedto condition blood exiting the organ circulatory compartment andentering the systemic circulation. Such conditioning is schematicallyillustrated in FIG. 1 as “therapy deactivation”, wherein the bloodconditioning apparatus deactivates therapy that has passed through thetarget organ in the organ circulation loop. Deactivation of thedelivered therapy may be beneficial prior to returning blood flow to thesystemic circulation to minimize or eliminate systemic impact of thetherapy.

An implementation of the complete organ isolation arrangementschematically set forth in FIG. 1 is illustrated in FIG. 2, whereinsystem 8 includes a venous catheter 10 having a distal portion 12 thatis positionable at a venous drainage structure 20 at a target tissuestructure (organ) 11. Distal portion 12 of venous catheter 10 includes afirst occlusion device 14 that is adapted to selectively substantiallyocclude venous drainage structure 20, and to thereby substantiallyocclude all venous drainage of tissue structure 11. Venous catheter 10further includes a perfusion port 16 that is operably disposed upstreamfrom first occlusion device 14, and a systemic port 18 operably disposeddownstream from first occluder device 14.

For the purposes of the present invention, the terms “upstream” and“downstream” refer to the natural, unaltered blood flow direction, suchas the natural, unaltered blood flow directions through arteries,organs, and veins. Therefore, the term “upstream” in a venous drainagestructure means in a relative direction toward the respective tissuestructure/organ from which venous blood flow is drained through suchvenous drainage structure. Therefore, even in the case of retrogradeperfusion (such as that illustrated in FIG. 2), a perfusion port (16)disposed “upstream from” an occlusion device (14) is intended to meanthat such perfusion port (16) is proximally located to the target tissuestructure (11) with respect to the occlusion device (14).

System 8, as illustrated in FIG. 2, further includes an arterialcatheter 30 having a distal portion 32 positionable at an arterialinflow structure 22 of tissue structure 11. Distal portion 32 ofarterial catheter 30 includes a second occlusion device 34 that isadapted to selectively substantially occlude arterial inflow structure22, and to thereby substantially occlude all arterial inflow of tissuestructure 11. Arterial catheter 30 further includes a drainage port 36that is operably disposed downstream from the second occlusion device34.

In some embodiments, second occlusion device 34 substantially occludesall arterial inflow to tissue structure 11, and first occlusion device14 substantially occludes all venous drainage from tissue structure 11.However, it is contemplated that system 8 may be employed for tissuestructures 11 having collateral circulation on one or both of thearterial and venous systems. Accordingly, the first and second occlusiondevices 14, 34 of system 8 may be employed to occlude only targetedvenous drainage structures and arterial inflow structures of tissuestructure 11. Moreover, while systemic port 18 is illustrated in FIG. 2as being associated with venous catheter 10, it is contemplated thatsystemic port 18 may be associated with either or both of venouscatheter 10 and arterial catheter 30.

System 8 further includes a blood conditioning apparatus 40 whichfluidly couples together perfusion port 16, drainage port 36, andsystemic port 18. Blood conditioning apparatus 40 is capable ofconditioning blood supply thereto as drainage flow 42 through drainageport 36 and drainage line 2, reperfusing at least a portion of drainageflow 42 through perfusion line 1 and perfusion port 16 as conditionedretrograde perfusion flow 44, and dispensing at least a portion ofdrainage flow 42 through systemic line 3 and systemic port 18 assystemic flow 46. As indicated above, a flow-volume adjusting mechanism48 may be employed to increase/decrease blood flow in the organcirculatory compartment to maintain desired blood flow and fluidpressures within the organ circulatory compartment. Consequently,flow-volume adjusting mechanism 48 is capable of permitting and/ormotivating blood flow either to the systemic circulatory compartment outthrough systemic port 18, or in from the systemic circulatorycompartment through systemic port 18 along systemic line 46.Consequently, blood flow may be bi-directionally processed throughsystemic line 46 to accommodate the adjustment controlled by flow-volumeadjusting mechanism 48 of blood conditioning apparatus 40. Suchbi-directionality is schematically depicted in FIG. 1. Typically,flow-volume adjusting mechanism 48 is required only in complete tissuestructure isolation embodiments of the present invention, such as thatillustrated in FIGS. 1 and 2, in which arterial inflow and venousoutflow from tissue structure 11 is substantially completely controlledby at least venous catheter 10 and arterial catheter 30 of system 8. Itis also to be understood that flow-volume adjusting mechanism 48 is nota required component of system 8, but rather an optional mechanism forcontrol of blood flow to and from the organ circulatory compartment. Itis also to be understood from the schematic depiction of FIG. 1 thatblood flow through the target organ, as driven by system 8, may beretrograde, antegrade, or alternating between retrograde and antegrade.For antegrade flow through the target organ 11, perfusion of conditionedblood may be dispensed by blood conditioning apparatus 40 through line2, and drained from organ 11 through line 1. It should therefore beunderstood that the roles of at least the perfusion and drainage linesof system 8 may be reversed for antegrade and/or bi-directional flowthrough target organ 11.

As depicted in FIG. 2, system 8 employs two separate catheters, 10, 30,and two vascular access points. In the illustrated embodiment, arterialcatheter 30 is a dual lumen balloon catheter, with second occlusiondevice 34 being an inflatable occlusion balloon as commonly utilized inthe art. A first lumen of arterial catheter 30 is drainage line 2, whilea second lumen may be utilized for balloon inflation and deflation. Thefirst and second occlusion devices 14, 34 may each be inflatableballoons to separate the organ circulation from the systemiccirculation, resulting in separated organ and systemic circulatorycompartments. Perfusion port 16 and drainage port 36 are open in theorgan circulatory compartment, while the systemic port 18 is open to thesystemic circulatory compartment. Venous catheter 10 may be a triplelumen balloon catheter, with a first lumen dedicated for perfusion line1, a second lumen dedicated for systemic line 3, and a third lumen forballoon inflation and deflation. In one embodiment, systemic line 3 maybe incorporated with venous catheter 10 in order to minimize thepossibility of arterial embolism.

Catheters 10, 30 may be inserted through any common venous or arterialaccesses, respectively, such as the femoral, internal jugular, orsubclavian vein, or the femoral or carotid artery. In a particularembodiment, arterial catheter 30 may be a stent delivery catheter or athrombectomy catheter having arterial access. To connect drainage port36 and drainage flow 42 to blood conditioning apparatus 8, a shunt 43may be employed.

For certain implementations, the arterial catheterization required forthe complete organ circulatory isolation system described in FIGS. 1 and2 may be undesirable for its potential complications of arterialembolism to the target organ itself or to other vital organs, and/or maynot be feasible in certain clinical situations, such as in an emergency.The present invention, therefore, also contemplates a partial organcirculatory compartment isolation using only venous access to performthe therapy delivery. Venous access may be achieved through minimallyinvasive techniques, and is relatively rapidly achievable, even in anemergency setting.

Partial organ circulatory isolation, unlike complete isolationtechniques described above, do not require arterial access. Perfusatefor therapy delivery may be applied retrogradedly through the venousdrainage structure of the target tissue structure (organ). In thisapproach, the organ experiences somewhat increased blood flow and fluidpressure. Veins typically exhibit relatively high elastic compliance,and are therefore well suited to accommodate the increased blood flowand pressure of the retrograde perfusion techniques of the presentinvention. Increased organ venous pressure may actually be advantageousin increasing hydrostatic pressure and tissue perfusion, therebyminimizing no-flow phenomena caused by an ischemic event, and increasingoxygenated blood flow to the post-arterial occlusive area. Partialcirculatory isolation may be performed by diverting normal venous flowthrough a venous drainage line to an extracorporeal blood conditioningapparatus to condition the blood (oxygenating, cooling, bioactive agentaddition, etc.) and perfusing the conditioned sanguineous materialthrough a perfusion line to the venous drainage structure of the targettissue structure. In this manner, the accessed vein is “arterialized” tosupply the target organ with additional oxygenated blood flow. Since thearterial flow to the target tissue structure contributes to the flowvolume of the venous drainage where the arterial inflow is not occluded,only a certain fraction of the venous drainage flow volume is returnedto the extracorporeal therapy delivery and reperfused to the targetorgan through the venous perfusion line. Excess venous blood volumecaptured by the venous drainage line of the present system may bedirected to the systemic circulation, and optionally through a therapydeactivation system prior to return to the systemic circulation. Aschematic representation of an embodiment of the present invention forpartial tissue structure circulatory isolation is provided in FIG. 3.System 60 includes a first venous access line 64 positionable at a firstvenous drainage structure 72 of a target tissue structure 61, and asecond venous access line 66 positionable at a second venous drainagestructure 74 of tissue structure 61. In one embodiment, first venousaccess line 64 is a first venous catheter having a distal portion 65that is positionable at first venous drainage structure 72 of tissuestructure 61. Distal portion 65 of first venous catheter 64 may includea first occlusion device 68 that is adapted to selectively substantiallyocclude first venous drainage structure 72. FIG. 4 provides a moredetailed illustration of the system 60 schematically depicted in FIG. 3.

Second venous access line 66 may be a second venous catheter having adistal portion 67 that is positionable at second venous drainagestructure 74. Distal portion 67 of second venous catheter 66 may includea second occlusion device 78 that is adapted to selectivelysubstantially occlude second venous structure 74 so as to, incombination with first occlusion device 68, establish an organcirculatory compartment of tissue structure 71 that is separate from thesystemic circulatory compartment. In some embodiments, however, firstand second catheters 64, 66 only partially occlude venous drainage oftissue structure 61, and are therefore useful in isolating at leastportions of tissue structure 61 for preferred conditioned bloodperfusion thereof.

In the schematic diagram of FIG. 3, first venous access line 64 mayaccommodate a venous perfusion line 1 for perfusion flow 80, whilesecond venous access line 66 may accommodate a drainage line 2 forvenous drainage flow 82. First and second catheters 64, 66 may include aperfusion port 76 operably disposed upstream from a respective one offirst and second occlusion devices 68, 78. First and second catheters64, 66 may further include a drainage port 77, and a systemic port 79that is operably disposed downstream from a respective one of first andsecond occlusion devices 68, 78.

System 60 further includes a blood conditioning apparatus 90 whichfluidly couples perfusion port 76, drainage port 77, and systemic port79 to one another at an organ circulatory isolation unit 92 of bloodconditioning apparatus 90. In this embodiment, blood conditioningapparatus 90 is capable of conditioning blood supplied thereto asdrainage flow 82 through drainage port 77 and drainage line 2 andreperfusing at least a portion of drainage flow 82 through perfusionline 1 and perfusion port 76 as conditioned retrograde perfusion flow80. Conditioning apparatus 90 is further configured to dispense at leasta portion of drainage flow 82 through systemic line 3 and systemic port79 as systemic flow 84. As with other embodiments of the presentinvention, it is to be understood that systemic line 3 terminating insystemic port 79 may be incorporated with either or both of first andsecond catheters 64, 66. Moreover, it is to be understood that either orboth of first and second catheters 64, 66 may include one or both ofperfusion line 1 terminating in perfusion port 76 and drainage line 2originating from drainage port 77.

In the illustrated embodiment, perfusate is directed to tissue structure61 and its capillary bed through perfusion line 1, and returns fromtissue structure 61 through venous drainage line 2 via venous collateralcirculation between first and second venous drainage structures 72, 74of tissue structure 61. In this manner, the two veins 72, 74 operate asa perfusion vein and a drainage vein, respectively. In some embodiments,a small negative pressure on drainage line 2 may be provided to drawmost of the venous blood flow of tissue structure 61 to drainage port77.

As described above with respect to the complete isolation embodiment,system 60, employing at least two venous access locations, may beemployed for either of complete or partial tissue structure circulationisolation. First and second catheters 64, 66 may be multiple lumenballoon catheters, wherein first and second occlusion devices 68, 78 maybe inflatable balloons, as is well known in the art. For the illustratedexample, first catheter 64 may be a dual-lumen catheter, with a firstlumen for profusion line 1, and a second lumen for transporting fluidfor inflation/deflation of balloon 68. In similar manner, secondcatheter 66 may be a triple-lumen catheter, with a first lumen fordrainage line 2, a second lumen for systemic line 3, and a third lumenfor transporting inflation fluid to inflatable balloon 78. Withocclusion devices 68, 78 deployed in an occluding condition, perfusionand drainage lines 1, 2 are open in the organ circulatory compartment,while the systemic line 3 is open to the systemic circulatorycompartment.

In the illustrated embodiment, drainage port 77 is disposed upstreamfrom a respective one of first and second occlusion devices 68, 78.However, it is contemplated that drainage port 77 may be disposeddownstream from first and second occlusion devices (in the systemiccirculatory compartment), particularly in applications where tissuestructure 61 possesses collateral venous drainage in addition to firstand second venous drainage structures 72, 74.

The multiple access catheter configuration of system 60 permitssimultaneous perfusion and drainage for continuous therapy delivery.Though continuous, the venous retroperfusion and drainage flows,separately, may be constant or cyclical, and may be regulated bysystemic or local hemodynamic or safety pressure set points monitored byblood conditioning apparatus 90 in a manner described in more detailhereinbelow.

Ideal tissue structure candidates for system 60 may include at least twomajor venous drainage lines. A particular example is the brain which hasvenous drainage to the left and right internal jugular veins, which arewell connected through intracranial venous sinuses. As a result,perfusion through one internal jugular vein may effectively perfuse bothsides of the brain, and venous return flow from both sides of the braincan be drained to another internal jugular vein, without significantincrease of intracranial or intracerebral pressure. Internal jugularvein catheterization is also a common intervention, such that system 60of the present invention may be readily accepted by practicingphysicians.

One example application of system 60 may be in providing therapeutichypothermia to global brain tissue. Full-time balloon inflation forfirst and second balloon catheters 64, 66 establishes an environmentconducive to localized brain cooling, and minimizes systemic cooling.One or more of catheters 64, 66 may be provided with a pressure sensor,such that the respective occlusion devices 68, 78 may be intermittentlydeflated to release potential backflow to the cerebral circulation. Inthis embodiment, conditioning by blood conditioning apparatus includescooling perfusion flow 80 to less than about 35° C. Moreover, bloodconditioning apparatus 90 may incorporate therapy deactivation, suchthat conditioning further includes warming systemic flow 84 tophysiologic temperature to avoid undesirable systemic cooling.

Another embodiment of the present invention is illustrated in FIG. 5,wherein first and second catheters 102, 104 are configured for venousaccess from an opposite direction as that described with respect tofirst and second catheters 64, 66. In particular, first catheter 102 maybe arranged such that first occlusion device 108 is distally disposedwith respect to perfusion port 110, with perfusion port 110 operabledisposed upstream from first occlusion device 108 (in the organcirculatory compartment). Perfusion flow 80 therefore is dispensed outfrom perfusion port 110 to perfuse tissue structure 111 in a retrogradedirection. In the embodiment illustrated in FIG. 5, second catheter 104includes a drainage port 112 disposed upstream from second occlusiondevice 118 (in the organ circulatory compartment), such that perfusionport 110 and drainage port 112 are open to the organ circulatorycompartment, while systemic port 114 is open to the systemic circulatorycompartment.

A further embodiment of the present invention is schematically depictedin FIG. 6, wherein system 120 includes a single venous access line thatis adapted to deliver localized therapy to an at least partiallyisolated target tissue structure 122. A more detailed depiction ofsystem 120 is illustrated in FIG. 7. The single venous access line maybe embodied in a venous catheter 124 having a distal portion 126 that ispositionable at a venous drainage structure 140 of tissue structure 122.Distal portion 126 of catheter 124 may include an occlusion device 128that is adapted to selectively substantially occlude venous drainagestructure 140. In one embodiment, occlusion device 128 may be deployedto substantially isolate venous circulation of tissue structure 122 fromthe systemic body circulation, so as to separate an organ circulatorycompartment from the systemic circulatory compartment (as illustrated inFIG. 7). In some embodiments, catheter 124 includes a perfusion port 132operably disposed upstream from occlusion device 128 for dispensingperfusate to the localized organ circulatory compartment. Catheter 124preferably further includes a drainage port 134 for capturing venousdrainage flow 144 to supply system 120 with blood flow for generating aconditioned perfusate. Drainage port 134 may be disposed upstream ordownstream from occlusion device 126, as desired per application.Embodiments utilizing drainage port 134 downstream from occlusion device128 may involve tissue structures 122 with collateral venous dischargeand/or intermittent deployment of occlusion device 128. In this manner,venous drainage from tissue structure 122 may be mediated to maintainfluid pressures at tissue structure 122 within acceptable limits.

The arrangement illustrated in FIG. 7 is an example organ circulatoryisolation configuration, wherein at least a venous drainage structure140 of tissue structure 122 may be continuously occluded by occlusiondevice 128, and wherein therapy delivered through perfusion line 1 andthrough perfusion port 132 may be substantially completely captured atdrainage port 134 upstream from occlusion device 128. As a consequence,perfused therapy is substantially maintained within the organcirculatory compartment, and does not contaminate the systemiccirculatory compartment.

System 120 further includes a blood conditioning apparatus 150 whichfluidly couples perfusion port 132 and drainage port 134 to one another.Blood conditioning apparatus 150 may be capable of receiving bloodsupply thereto as drainage flow 144 through drainage port 134, andreperfusing at least a portion of drainage flow 144 through perfusionport 132 as conditioned retrograde perfusion flow 132. The conditioningof conditioning apparatus 150 may include providing cooling to generateperfusion flow 142 at less than about 35° C.

In some embodiments, catheter 124 includes a systemic port 136 operablydisposed in the systemic circulatory compartment, and fluidly connectedto perfusion port 132 and drainage port 134 through blood conditioningapparatus 150. Blood conditioning apparatus 150 may be capable ofdispensing at least a portion of drainage flow 144 through systemic port136 as systemic flow 146. Systemic port 136 is preferably arranged todispense systemic flow 146 into the systemic circulatory compartment.Prior to dispensing systemic flow 146 into the systemic circulatorycompartment, blood conditioning apparatus 150 may condition systemicflow 146 by deactivating systemic flow 146. In some embodiments,deactivation by blood conditioning apparatus 150 includes warmingsystemic flow 146 to physiologic temperature. In this manner,hypothermic therapy delivered to the targeted tissue structure 122within the organ circulatory compartment may be “deactivated”, orwarmed, prior to release to the systemic circulatory compartment, suchthat the therapeutic hypothermia is localized to the target tissuestructure 122, and does not contaminate the systemic circulatorycompartment.

System 120 illustrated in FIG. 7 provides retrograde therapy delivery tothe targeted tissue structure 122, and controls venous drainage throughdrainage port 134 to direct venous drainage flow 134 to bloodconditioning apparatus 150. In some embodiments, single catheter 124 maybe positioned within a venous drainage structure of tissue structure 122that accounts for substantially all venous drainage from tissuestructure 122. An example embodiment is in therapy delivery to themyocardium by placement of catheter 124 at the coronary sinus, such thatocclusion device 128 occludes substantially all venous drainage from themyocardium. Such an arrangement prevents or minimizes contamination ofthe therapy between the coronary and systemic circulations. Occlusiondevice 128, which may be an inflatable balloon of a balloon catheter,may be continuously deployed in contact with the coronary sinus wall toestablish true compartmentalization of the coronary circulatory system,as separate from the systemic circulatory compartment.

The embodiment illustrated in FIG. 8 exhibits similar functionality tothe embodiment illustrated in FIG. 7, but with a somewhat modifiedconfiguration. In particular, single catheter 160 may be arranged withsystemic port 168 operably disposed distally of occlusion device 170,such that systemic flow 146 is dispensed through systemic line 3 and outfrom systemic port 168 into the systemic circulation. In thisembodiment, occlusion device 170 substantially completely isolatesvenous drainage of the target organ from systemic circulation, whereinocclusion device 170 substantially occludes a main, or only, venousdrainage structure 140 of the target tissue structure 122. Perfusionflow 142 is dispensed at perfusion port 162 proximally of occlusiondevice 170, but nevertheless within the venously isolated organcirculatory compartment. Likewise, venous drainage from tissue structure122 through drainage port 164 for drainage line 144.

In either of the embodiments illustrated in FIGS. 7 and 8, the venousdrainage of the organ circulatory compartment may be substantiallyisolated from the systemic circulatory compartment. Consequently,therapy may be delivered through perfusion line 1 to the organcirculatory compartment for localized therapy of the targeted tissuestructure 122. Due to the substantial isolation of venous drainage fromtissue structure 122, the delivered therapy may be kept separated fromthe systemic circulatory compartment, and processed through the bloodconditioning apparatus prior to return to the systemic circulatorycompartment. Targeted therapy may therefore be accomplished in alocalized manner to the target organ/issue structure, without incurringundesired side effects through contamination of the therapy to systemiccirculation.

In addition to providing localized therapy to a target tissue structure,the configurations described above provide a simple, single-catheterdevice for accomplishing the localized therapy. The single catheterarrangement requires only a single venous access, which may be rapidlyperformed, even under emergent situations. Distal placement of thesingle catheter is also facilitated through the requirement of only asingle occlusion device strategically positioned to selectivelysubstantially occlude venous drainage from the targeted tissuestructure.

It is also contemplated by the present invention that the perfusion anddrainage lines 1,2 may be combined into a single lumen for communicationwith a combined perfusate/drainage port operably disposed in theselectively substantially isolated organ circulatory compartment. Afirst example of such an embodiment is illustrated in FIG. 9, in whichcatheter 190 includes a combined perfusion/drainage lumen 192communicating with a combined perfusion/drainage port 194 disposed inthe organ circulatory compartment, and selectively substantiallyisolated from the systemic circulatory compartment by occlusion device202. In the embodiment illustrated in FIG. 9, combinedperfusion/drainage port 194 is operably disposed distal to occlusiondevice 202. The embodiment of FIG. 10 provides for a distally locatedocclusion device 212 with respect to combined perfusion/drainage port214 of combined perfusion/drainage lumen 216. Combinedperfusion/drainage port 214 of FIG. 10 is also disposed upstream fromocclusion device 212, so as to communicate with the selectivelysubstantially isolated organ circulatory compartment.

In either of the embodiments illustrated in FIGS. 9 and 10, theperfusion and drainage flows 196, 198 are separated in a flow separatordevice 200 within the blood conditioning apparatus. Flow through lumens192, 216, therefore, is bi-directional, in perfusing in a retrogradedirection, and permitting antegrade drainage of venous flow to the bloodconditioning apparatus. Typically, a combined perfusion/drainage lumen192, 216 may be employed for relatively larger-volume tissuestructures/organs, particularly where the tissue structure volume islarger than the volume of the combination perfusion/drainage lumen 192,216. A benefit of combining the perfusion and drainage lines 196, 198into a single lumen 192, 216 is the reduction of flow resistance as aresult of an increased luminal diameter. Such reduced flow resistancemay facilitate increased perfusion and drainage flow. By contrast, theseparated perfusion and drainage lumens of FIGS. 7 and 8 may beadvantageously employed in certain applications to prevent a dead spacefor therapy exchange, particularly in small-volume target organs.Moreover, separating the perfusion line 1 from the drainage line 2allows for the respective perfusion and drainage flows to have someoverlap, and could therefore theoretically optimize or maximize therapydelivery. It is contemplated, therefore, that the present inventionencompasses at least the illustrated configurations.

The systemic line 3, which communicates systemic port 199 to thesystemic circulatory compartment may be variously arranged. For example,the systemic port location may vary from immediately proximal to thecatheter insertion site, to a location adjacent to the operable locationof the occlusion device, such as within the venous drainage structure ofthe organ downstream from the deployed occlusion device.

Each of the example embodiments of FIGS. 7-10 conceptually follow theschematic depiction of a single-vein access system illustrated in FIG.6. Such a system may employ partial or complete isolation of the targettissue structure/organ 122, wherein arterial occlusion may or may not beemployed in combination with the single venous access approach. Thearrangement of the schematic diagram of FIG. 6, however, utilizes bothvenous perfusion and drainage in a single vein/venous drainagestructure. In some embodiments, perfusion and drainage do not occursimultaneously, and are instead cyclically controlled for bi-directionalflow, alternating between perfusion to the organ circulatorycompartment, and drainage from the organ circulatory compartment. Thevenous retroperfusion line perfuses a therapy through the venousstructure to reach the target tissue structure capillary bed and tissue.Such venous retroperfusion may result in elevated intramural andintravenous pressure of the target organ/tissue structure. The venousdrainage line is, therefore, responsible for maintaining the intramuraland intravenous pressure within a designated safety range, and also forinsuring adequate tissue circulation. The venous perfusion/drainagecycle may correspond to the localized organ circulatory cycle, such asthe cardiac cycle for the myocardium, or a wave form cycle for otherorgans, such as the liver. That is, the drainage cycle may be activatedby, for example, physiological signals such as an electrocardiogramsignal (with appropriate time offset from R wave or both or either ofsurface or intracardiac electrocardiogram), local hemodynamicinformation (local flow or pressure waveforms), or a pressure set point,or the combination of different signals. The balance between theperfusion and drainage phases may be governed or driven by the bloodconditioning apparatus, as described in greater detail hereinbelow.

The single-vein access isolation technique may be used with a variety oforgans or other tissue structures that have major venous portaldrainage. Example tissue structures include the coronary sinus, theinternal jugular veins of the brain, the hepatic veins, and the renalvein. In the case of therapy delivered to the liver, for example, alocalized therapy for each lobe may be possible, as the hepatic venoussystem is divided into right, middle, and left hepatic veins, which areall accessible from the inferior vena cava. A primary benefit of thesingle-vein access technique is the simplicity of intervention, inrequiring only one catheter accessed through a commonly utilized venousaccess point. In embodiments utilizing intermittent perfusion, thetherapy delivery may require relatively larger perfusion flow volumecompared to the organ volume, possibly resulting in elevated intravenousand intramural pressures. It is therefore desired that pressuremonitoring be incorporated with such systems to maintain pressureswithin a safety range.

The embodiments of FIGS. 7-10 may operate with full-time occlusion of avenous drainage structure of the target tissue structure. Such full-timeocclusion may be accomplished by inflation of an inflatable balloonagainst the venous walls of the venous drainage structure. The full-timeocclusion is facilitated by positioning the drainage port upstream fromthe occlusion device, such that venous drainage from the at leastpartially isolated tissue structure may be drained to the bloodconditioning apparatus for reperfusion of conditioned blood flow to theorgan circulation compartment and deactivation and dispensation to thesystemic circulation.

A variation of the embodiments described with reference to FIGS. 3-10 isillustrated in FIGS. 26-28. In particular, system 1060 includes a firstvenous access line 1064 positionable at a first venous drainagestructure 1072 of a target tissue structure 1061, and a second venousaccess line 1066 positionable at a second venous drainage structure 1074of tissue structure 1061. System 1060 further includes a bloodconditioning apparatus 1090 having an organ circulatory isolation unit1092. Blood conditioning apparatus 1090 may preferably be programmed toselectively operate in one of three operating modes, with a firstoperating mode dispensing an entirety of drainage flow from venousdrainage line 1066 as systemic flow 1084 to the systemic circulation1086. In this mode of operation, dispensation of drainage flow may berouted through a therapy deactivation module 1083 to condition ordeactivate systemic flow 1084 prior to delivery to systemic circulation1086. In this mode of operation, blood supply for the perfusion flow isderived from systemic or external sources, rather than being directlyrecirculated from the drainage flow, and is therefore considered an“open loop” system.

A second mode of operation for blood conditioning apparatus 1090involves reperfusing at least a portion of the drainage flow as theentirety of the conditioned retrograde perfusion flow. In this operatingcondition, no non-recirculated flow is supplied to the perfusion port,and is therefore considered a “closed loop” system. A third mode ofoperation for blood conditioning apparatus 1090 is a blend of the firstand second modes, wherein some portion of the perfusion flow is derivedfrom systemic or external sources. The recirculated flow may be mixedwith the systemic/external source flow to constitute the perfusion flow,or may instead be delivered as reperfusion flow in designated modesalternating or otherwise differing from the systemic/external sourceperfusion flow. The selective recirculation flow of the second and thirdoperating conditions of blood conditioning apparatus 1090 is depicted bythe dashed line for recirculation flow 1094.

System 1120 of FIG. 27 is analogous to system 120 of FIG. 6, butschematically depicts three operational modes of blood conditioningapparatus 1150, as described above with reference to blood conditioningapparatus 1090.

A schematic flow diagram of system 1120 is illustrated in FIG. 28 asused in an application for therapeutic cooling of the myocardium. Inthis example arrangement, perfusion flow is sourced from a systemic veinand driven to an extracorporeal therapy delivery module, which, in thisapplication, includes a cooling heat exchanger, such that the “therapy”is cooling of the blood. A retroperfusion pump is controlled by a signalindicating pressure in the coronary sinus to maintain appropriateretroperfusion flow rates. A phase-gauged retroperfusion valve opens atthe termination of myocardium systole to permit retroperfusion flow intothe coronary sinus through a coronary sinus balloon catheter duringdiastole of the myocardium.

Drainage flow from the coronary sinus is permitted by a phase-gaugeddrainage valve, which is controlled to open at the initiation ofmyocardium systole. A drainage pump may be provided to drive thedrainage flow to a therapy deactivation module, which, in thisapplication, is a warming heat exchanger. The warmed drainage flow isdelivered to the systemic circulation, ideally at or near normal bodytemperature. In some embodiments, a thermocouple may monitor systemiccirculation temperature. If the systemic circulation temperature dropsbelow a predetermined threshold, a back-up systemic pump may drivesystemic circulation back through the warming heat exchanger. If thesystemic circulation temperature exceeds a predetermined threshold, atemperature control unit may communicate and control the warming heatexchanger to operate at a lower temperature. In some cases, the heatexchanger may be operated to cool the drainage flow and/or the systemiccirculation to adjust the systemic circulation temperature to a normalphysiological range, or even to a temperature below normal physiologicaltemperature, to induce systemic therapeutic hypothermia. Thus, the heatexchanger on the systemic flow may act as a secondary flow conditionerto supply conditioned blood to the systemic circulatory compartment. Theso-conditioned blood may provide a therapy to the systemic circulatorycompartment, and the therapy may be the same or different than thatdelivered to the tissue circulatory compartment through the perfusionport. It should be understood, however, that alternative controlarrangements for delivering conditioned retroperfusion flow to a targettissue structure, and for returning deactivated drainage flow to thesystemic circulation are contemplated by the present invention.

The retroperfusion and drainage valves described above may be commonlyemployed in certain applications of the present invention, particularlyfor single-vein partial organ isolation, wherein the retrogradeperfusion and drainage occur in a single major venous drainage structureof the target tissue structure (organ receiving treatment). The valvestherefore preferably operate in concert to manage blood flow to and fromthe target tissue structure. A control mechanism is therefore linked toeach of the retroperfusion valve and the drainage valve to selectivelydrive their opening and closing, respectively. The control mechanism maybe driven by a predetermined timing sequence, or may receive inputsignals from the target tissue structure that dictate the timing ofcontrol transmissions to the respective valves. In the case of thetreatment of the myocardium through a single venous structure, asillustrated in FIG. 28, the control system may preferably receivesignals from an electrocardiogram monitoring the R-wave of themyocardium.

An example R-wave signal is illustrated in FIG. 29, with “S” denotinginitiation of systole, and “D” indicating diastole. A basic approach tovalve control is to deliver retrograde perfusion to the organ duringdiastole (D→S), and to allow for venous drainage during systole (S→D),and to perform and repeat such process once for every cardiac cycle. Inthis basic approach, the retroperfusion valve would be controlled opento permit perfusion during the period of D1→S1, and then close at theinitiation of systole (S1), accompanied by the controlled opening of thedrainage valve during systole, which is indicated on the annotatedR-wave of FIG. 29 as S1→D2, the end of the first cardiac cycle. For thepurposes hereof, the flow control algorithm for the control mechanismoperating the retroperfusion and drainage valves is considered the“perfusion-to-drainage ratio” (P2D Ratio). Examples of different P2DRatios contemplated by the present invention are presented in thefollowing Table 1:

TABLE 1 Examples of different P2D Ratios Timing P2D Ratio PerfusingHolding Draining 1:0:1 D1→S1 — S1→D2 2:0:2 D1→S2 — S2→D4 1:0:2 D1→S1 —S1→D3 1:1:1 D1→S1 S1→S2 S2→D3 2:0:1 D1→S2 — S2→D3 2:1:1 D1→S2 S2→S3S3→D4 2:1:2 D1→S2 S2→S3 S3→D5 2:0:3 D1→S2 — S2→D5 3:0:1 D1→S3 — S3→D43:0:2 D1→S3 — S3→D5

As indicated in the above table, certain control algorithms contemplatedby the present invention permit certain control operation sequences thatspan more than a single cardiac cycle. Certain control algorithmsinvolve a period of time during which both the retroperfusion anddrainage valves are closed (Holding). Moreover, certain of the controlalgorithms described in Table 1 avoid drainage valve opening altogether.In some embodiments, the mathematical sum of the (Holding) and the(Drainage) numbers may not exceed the (Perfusion) number. However,various P2D Ratio control algorithms are contemplated as being useful inthe present invention.

It is to be understood that perfusion (retroperfusion valve open) timeperiods that span across a systole cycle may typically involve aretroperfusion valve closure during systole. Upon initiation ofdiastole, however, the retroperfusion valve may be controlled to an openposition once again. The various P2D control algorithms contemplatevarious scenarios for best treating the subject tissue structure, suchthat P2D ratios not shown in Table 1 may nevertheless be useful in thepresent invention.

In another embodiment of the present invention illustrated in FIGS. 11Aand 11B, a single access venous catheter 220 includes a perfusion line 1terminating in a perfusion port 222 that is operably disposed upstreamfrom occlusion device 230. Catheter 220 further includes a drainage line2 receiving venous drainage flow through drainage port 224. Excessdrainage flow may be returned to the systemic circulation at systemicline 3 through systemic port 221. Drainage port 224 and systemic port221 are operably disposed in the systemic circulation, which isselectively and at least partially isolated from the organ circulatorycompartment upstream from occlusion device 230. Such an arrangement mayprovide a “pseudo-isolated” therapy delivery, in which therapy deliveredthrough perfusion port 222 at the organ circulatory compartment may bevenously drained to the systemic circulation without first being routedthrough blood conditioning apparatus for deactivation. Drainage port 224and/or systemic port 221 may be operably positioned in the systemiccirculatory compartment proximally to the site of catheter insertion, ormay be more distally disposed, such as more proximal to occlusion device230. There is no requirement that drainage port 224 and systemic port221 be operably positioned in proximity to one another. The sequence ofdrainage port 224 and systemic port 221 typically depends on the localdistribution of venous braches. In some embodiments, drainage port 224may be upstream from systemic port 221.

Occlusion device 230, which may be an inflatable balloon, may beselectively inflated and deflated in concert with a venous drainagecycle of the target organ. In such a manner, occlusion device 230 may beselectively deflated during the natural venous drainage cycle to permitvenous drainage out from the organ circulatory compartment, andsubsequently re-inflated to occlude the venous drainage structure tofacilitate retrograde perfusion between drainage cycles. In the exampleof the target organ being the myocardium, occlusion device 230 may be aninflatable balloon operably positioned at the coronary sinus. Balloon230 may be operated to deflate during the coronary venous drainage(systole). Re-inflation of balloon 230 may occur during diastole tofacilitate retroperfusion into the myocardium from perfusion port 222 atthat time. Because balloon 230 is deflated during systole, therapydelivered through perfusion port 222 may be allowed to contaminate thesystemic circulation to some extent. However, drainage port 224 may bearranged to continuously or cyclically collect contaminated systemicvenous blood flow, and deactivate the delivered therapy at the bloodconditioning apparatus for reentry to the systemic circulation atsystemic port 221. In the case of therapeutic hypothermia of themyocardium, the deactivation performed by the blood conditioningapparatus may be to warm contaminated systemic blood flow and returnsystemic flow 3 at or above physiologic temperature. This methodcompensates for the therapy contamination permitted through the cyclicdeflation of balloon 230.

Another embodiment of the present invention is illustrated in FIG. 12,wherein single access venous catheter 250 includes a perfusion line 1terminating in a perfusion port 252 that is operably disposed upstreamfrom occlusion device 260 in a venous drainage structure of a targetorgan/tissue structure. As such, perfusion port 252 may be operablydisposed in an organ circulation compartment that is at least partiallyseparated from the systemic circulation by occlusion device 260.Catheter 250 further includes a drainage line 2 collecting venousdrainage flow through drainage port 254. Drainage line 2 may comprise alumen having drainage port 254 disposed at any desired location, but maybe preferably disposed along a venous pathway defined by catheter 250 ata location between the site of catheter insertion and the operatingposition of occlusion device 260. Drainage port 254 may be disposed inthe systemic circulation at least partially separated from the organcirculation compartment in which perfusion port 252 is operablydisposed.

Occlusion device 260 may be operated in a similar fashion as thatdescribed with respect to occlusion device 230 of catheter 220, whereinocclusion device 260 may be deployed in an occluding conditionintermittently to permit cyclic venous drainage flow out from the organcirculatory compartment. The arrangement of FIG. 12 facilitates directtherapy delivery to the target tissue structure/organ. As with theembodiment of FIG. 11, perfusion through perfusion port 252 may bedelivered in a retrograde direction within a venous drainage structureof a target organ, and such retroperfusion may be phased to be performedduring a non-flow period of cyclical venous drainage flow. For example,perfusion to the myocardium through perfusion port 252 may be performedduring diastole, and may be ceased during systole. It is to beunderstood that such phasing perfusion may be performed in any of theembodiments of the present invention. The device of FIG. 12 does notinclude therapy deactivation by the blood conditioning apparatus, butnevertheless supplies perfusate at perfusion line 1 with conditionedblood, including, for example, being oxygenated and cooled. In thismanner, perfusion line 1 may supply ischemic tissue with oxygenated andcooled blood for therapeutic treatment thereof. Without deactivation,the perfused therapy may affect systemic circulation over a period oftime. However, such a system may be useful for relatively shortduration, such as during PCI to re-establish vascularisation andarterial blood flow to an affected tissue structure.

It is to be understood that the devices described in FIGS. 11 and 12 maybe used in a variety of tissue structures/organs. An example applicationis delivery of the single-access catheter to the jugular vein to providelocalized therapy to the intracranial venous sinuses. In such anembodiment, the perfusion port is disposed upstream from the deployedocclusion device, and perfusate may venously drain from the intracranialvenous sinuses through another of the jugular veins. With the existenceof collateral venous drainage, the occlusion device need not becyclically inflated/deflated, and may instead be continuously deployedin an occlusive condition. The drainage port and systemic port forjugular vein access may be operably positioned in the systemiccirculation where appropriate.

Any of the embodiments of the present invention may be employed asadjunctive therapy to, for example, an arterial intervention such as PCIfor heart attack treatment. In the case of an adjunctive arterialintervention, an additional drainage line may be established to captureretrograde perfusate at the arterial side of the target tissuestructure, and return at least a portion of the captured perfusate tothe blood conditioning apparatus for reperfusion and/or dispensation tothe systemic circulation. The additional drainage line may beincorporated with, for example, a stent delivery catheter or athrombectomy catheter, so that arterial intervention with such cathetersprovides a convenient platform for also capturing perfusion flow fromone or more separate venous catheters of the present invention. Theadditional drainage at the arterial side may be delivered to a bloodconditioning apparatus of the present invention through a shunt or otherline that is capable of drawing the reverse-flow drainage out from theadditional drainage line. In some embodiments, an arterial suction pumpmay be employed to provide the necessary suction to draw the additionaldrainage to the blood conditioning apparatus. The suction effect may beenhanced with the use of an occlusion device in connection with thearterial drainage line, so as to substantially compartmentalize orseparate the arterial circulation of the tissue structure from thesystemic arterial circulation. The occlusion device may be operablydisposed upstream from the arterial blockage, and may be operablypositioned substantially upstream from the arterial blockage in order tominimize risk of inadvertent disruption of the blockage. Conventionalthromboectomy catheters typically require positioning in close proximityto the arterial blockage, which can cause inadvertent breakage of theclot and/or plaque. Some thrombectomy catheters are even required topass through the blockage in order to position a blood filter downstreamof the blockage.

A unique benefit of this arrangement is to effectively inhibit clotand/or plaque debris from flowing downstream from the arterialintervention site. Instead, any debris is captured within the isolatedorgan circulatory compartment, and transferred to the blood conditioningapparatus for removal from the systemic circulation.

As indicated above, the catheters of the present invention may beequipped with various sensors, such as pressure, temperature, orchemical sensors, including direct organ electrical signal orelectrogram sensors, to provide feedback control to ensure operatingconditions within designated safety ranges. For example, pressuresensors may be disposed in the organ circulatory compartment to monitorthe pressure therein, and therapeutic sensors, such as temperaturesensors, chemical sensors, and the like, may be operably disposed at ornear the drainage port for optimal feedback control.

One or more fixation mechanisms may be included with the catheters ofthe present invention to provide additional catheter stability, and tosecure the catheter and occlusion device positions that are crucial forthe isolation of the organ circulatory compartment. Such fixationmechanisms may be useful to prevent catheter dislodgement during, forexample, programmed occlusion device deployment and collapse. Examplefixation mechanisms are illustrated in FIGS. 13A and 13B. Fixationmechanisms 275, 277 may be expandable/retractable stents or coils. Asillustrated in FIG. 13B, a pre-shaped coil-like catheter 280 may bestretched by a guide wire during catheter insertion and removal, and maybe integrated in the catheter design. For multiple lumen catheters, onlya single lumen may be pre-shaped, in the configuration illustrated inFIG. 13B.

The systems of the present invention are preferably adapted to delivertherapy to a target tissue structure through a perfusion line, localizethe therapy to the specific target tissue structure, regulate theorgan's circulatory flow volume, and deactivate the delivered therapyprior to re-entry to the systemic circulation through the systemic line.A schematic diagram of an extracorporeal blood conditioning apparatus ofthe present invention is illustrated in FIG. 14, wherein bloodconditioning apparatus 300 includes a therapy delivery module 310, atherapy isolation module 320, and a therapy deactivation module 330. Theschematic flow diagram of FIG. 14 illustrates example components of eachmodule 310, 320, 330, and the fluid flow direction and connectivity, aswell as example control pathways.

Localized therapy delivery provided by the present invention may includedrugs, chemotherapy, cell or gene therapy, and/or physical treatmentmodality (e.g. therapeutic hypothermia). In addition, localized therapydelivery may include oxygenation in order to increase or ensure adequateoxygen supply of the target tissue structure. Therefore, therapydelivery module 310 may include one or more therapy delivery mechanismsincluding, for example, (i) external supplement 312 for supplementaldrug or cell therapy, including chemotherapy or other supplements, (ii)oxygenation 314, and (iii) temperature control 316. External supplement312 may include a flow control infusion pump (not shown) that may besynchronized to the perfusion flow 1, or independently controlled.Oxygenation 314 may be provided through a conventional membraneoxygenator or through the supply of hyperbaric aqueous oxygen, orcombinations thereof. Temperature control 316, which may receive inputsignals from a temperature sensor within drainage line 2, providestherapeutic temperature to the target tissue structure. Such therapeutictemperature may include cooling for therapeutic hypothermia, or warmingfor countering the therapeutic hypothermia. As illustrated in FIG. 14,therapy delivery module is adapted to deliver perfusate to the venousaccess line (perfusion line 1).

A detailed exemplary flow diagram for therapy delivery module 310 isillustrated in FIG. 15. In the illustrated embodiment, therapy deliverymodule 310 includes a blood reservoir 315, an air/clot filter 317, and aperfusion pump 318 to drive the conditioned perfusate to the targettissue structure through perfusion line 1. In some embodiments, thecomponents of therapy delivery module 310 are contained within adisposable blood circuit cartridge.

Therapy isolation module 320 is fluidly coupled to drainage line 2 ofthe catheter, and is adapted to control both the absolute and relativedelivery and drainage of perfusate to and/or from the localized targettissue structure using the catheter in a manner that provides perfusateto substantially only the target tissue structure. In some embodiments,the drainage flow may exceed perfusion flow through perfusion line 1. Insuch embodiments, isolation unit 320 is responsible for maintainingoptimal perfusion flow and safe intravascular or intravenous pressurewithin the target tissue structure. Therapy isolation module 320therefore may be adapted to monitor flow volumes and intravascularpressure from the perfusion and drainage lines 1, 2, and diverting anyexcess flow to therapy deactivation module 330. As indicated in FIG. 14,drainage flow may be monitored and tested for diagnosis or diseaseprogression monitoring, such as in monitoring cardiac enzymes for thediagnosis of heart attack.

An example flow diagram of therapeutic isolation module 320 isillustrated in FIG. 16. The embodiment of FIG. 16 includes a bloodthinner addition mechanism to minimize clotting in the extracorporealloop, a drainage pump 324, and a flow controller 326 for controllingdivision of flow and flow rate to each of therapy delivery module 310and therapy deactivation module 330.

Where therapy isolation module 320 determines that drainage flow throughdrainage line 2 to be of a larger magnitude than the desired perfusionflow through perfusion line 1, a portion of the drainage flow isdirected to therapy deactivation module 330 as excess flow. Before suchexcess flow is returned to the systemic circulation as systemic flowthrough systemic line 3, any remaining therapy agents or characteristicswithin the excess flow may be deactivated by therapy deactivation module330 to prevent or minimize undesired systemic effects of such therapyagents or characteristics. The deactivation process depends upon thespecific therapies delivered by therapy delivery module 310, and may beperformed through internal deactivation and/or external deactivation.

Internal deactivation may include direct metabolizing (i.e. artificialliver) and dialysis (i.e. artificial kidney) for deactivation oftherapeutic drugs and/or chemotherapy. The metabolizing methods employedmay be specific to certain therapeutic agents, while the dialysis methodmay be more generally applied to a wide range of therapeutic agents. Inthe event that removal of the therapeutic agents through internaldeactivation is insufficient, external deactivation may be appliedthrough the addition of counter-balance antagonistic agents to theadministered bioactive agents. Internal deactivation applies to removingone or more bioactive agents from the blood, while external deactivationsupplies counteracting agents which interact with the systemiccirculation. In some embodiments, the dialysate from the internaldeactivation dialysis of therapy deactivation module 330 may be used fordiagnosis or disease monitoring during the therapy administration.Moreover, systemic drug or fluid supplements may be administered throughtherapy deactivation module 330 as a convenient vascular accesslocation.

Internal deactivation may further include a cell separator to reharvestcells used in cell-based therapy, and recycle the reharvested cells totherapy delivery module 310. Therapy deactivation module 330 may includea temperature control device 332 for modifying the temperature of theexcess flow, such as to physiologic temperature for dispensation throughsystemic line 3. For therapeutic hypothermia applications, in whichtherapy delivery module 10 perfuses cooled perfusate to the targettissue structure, temperature control device 332 may be adapted torewarm the excess flow to a physiologic temperature prior to return ofthe systemic flow to the systemic circulation. In this manner, thetherapeutic hypothermia may be substantially isolated to the targettissue structure, while the remainder of the systemic circulation issubstantially unaffected by such therapeutic hypothermia. The body orsystemic temperature may therefore be independently controlled from thetarget tissue temperature. A feedback loop for the deactivatingtemperature control device 332 may be independent from the target tissuestructure temperature control, such as by receiving body/systemictemperature signals from a sensor located within the systemiccirculation.

A flow diagram of an exemplary therapy deactivation module 330 of thepresent invention is illustrated in FIG. 17. While the therapydeactivation module flow loop may be a passive flow, as driven bydrainage pump 324, a systemic pump 334 may optionally be included toassist in flow direction control.

Though blood conditioning apparatus 300 is illustrated with a therapydeactivation module 330, it is to be understood that certain embodimentsof the blood conditioning apparatus of the present invention need notinclude such therapy deactivation module 330. In particular, evenwithout the therapy deactivation performed by therapy deactivationmodule 330, the target tissue structure/organ isolation obtained throughthe catheter arrangement of the present invention facilitates arelatively large organ-to-systemic concentration gradient. The localizedtherapy delivery may itself be considered a “passive” therapydeactivation, in that contamination of excess flow or collateralcirculation is diluted by the large systemic blood volume, while at thesame time the therapy concentration in the target tissue structurereaches a high therapeutic level.

In one embodiment of the present invention, a delivery machine 400 maybe provided to control the blood conditioning apparatus and the one ormore catheters associated with the blood conditioning apparatus in orderto deliver therapy to, and to drain some or all therapy from, thelocalized target tissue structure in a manner that provides therapydelivery to substantially only the localized target tissue structure. Anexample embodiment of delivery machine 400 is illustrated in FIG. 18,which is configured to connect and operate the therapy delivery module,the therapy isolation module, and the therapy deactivation module.Machine 400 may be arranged to facilitate blood conditioning andtransfer without itself contacting the patient's blood. For example,while not contacting blood, machine 400 may include an oxygen supplyunit, one or more temperature control units, non-contact blood pumps andflow-direction control, and internal deactivators.

Oxygen supply for oxygenating the perfusate may be supplied from aportable oxygen tank at machine 400, or a standard oxygen line from thefacility, directly connected to an oxygenator 314 in therapy deliverymodule 310 within a treatment cartridge 410. In some embodiments,treatment cartridge 410 is operably engagable to machine 400, and may bethe blood-contacting portion of the system, such that treatmentcartridge 410 may be disposable. In place of, or in addition to theoxygen tank or facility oxygen line, machine 400 may include ahyperbaric aqueous oxygen solution mixing unit (not shown), which isadapted to inject oxygen-saturated saline to perfusion line 1.

The temperature control units 316, 332 may use distilled water as a heatexchanging media, with the heat exchangers disposed in treatmentcartridge 410. Heating and cooling performed by temperature controlunits 316, 332 may be performed by a thermal-electric device which maybe controllably switched between heating or cooling by alternating theelectrical current. Confined in the tubing in cartridge 410 to preventcontamination with machine 400, the blood flow may be driven by arolling or peristaltic pump on machine 400. Such pump may also controlblood flow direction.

As indicated above, treatment cartridge 410 may include one or more oftherapy delivery module 310, therapy isolation module 320, and therapydeactivation module 330. In one embodiment, treatment cartridge 410includes each of modules 310, 320, 330. Cartridge 410, therefore,embodies functionality that may be carried through the facilities ofmachine 400. Machine 400 may be specifically configured to operablyreceive treatment cartridge 410 in a quick-connect/disconnect manner,with connections for, e.g., oxygenation, temperature control, fluidpumping, and therapy deactivation connections may be automaticallyestablished upon fitment of treatment cartridge 410 into operatingengagement with machine 400. FIGS. 19 and 20 illustrate exampleself-engaging mechanisms for pump heads 416, 418 of treatment cartridge410 to be operably engagable with rolling pump 422 of machine 400. FIG.19A illustrates cartridge 410 prior to operable engagement with machine400, while FIG. 19B illustrates the interaction between rolling pump 422of machine 400 with pump head 416 of cartridge 410 subsequent tooperable engagement of cartridge 410 to machine 400. In a particularembodiment, operable engagement may include physical engagement ofcartridge 410 to a receptacle of machine 400.

An alternative example arrangement is illustrated in FIGS. 20A-20C, inwhich pump head 418, which may be a blood circuit within disposabletubing, may be operably engaged with rolling pump 422 of machine 400 ina top-down approach. In each of the embodiments illustrated in FIGS. 19and 20, rollers 424 of rolling pump 422 operably engage pump head 416,418 to cause flow of fluid through the blood circuit.

The temperature control devices of cartridge 410 may incorporatenegative pressure induced in the heat exchanger compartment to avoidcontamination from the heat exchanging fluid into the blood flow. Incase of a leak on the heat exchanger loop, blood flow is drawn to theheat exchanger compartment, rather than vice versa. A hemoglobindetector may also be equipped in the heat exchanger compartment tomonitor any potential leaks. In any event, abrupt pressure changes inboth the heat exchanger and blood flow compartments may be used as anindication for system leakage.

External supplement devices may connect directly to cartridge 410, whichcartridge 410 may connect directly to the catheters of the presentinvention. In the event that a cell separator device is included,cartridge 410 may employ a line transferring the cells to therapydelivery module 310 from the cell separator in the therapy deactivationmodule. In the event that therapy deactivation module 330 includes ametabolizer or dialyzer, cartridge 410 may include an exhaust line forthe metabolite dialysate.

An example control circuit summary for a blood conditioning apparatus ofthe present invention is illustrated in FIG. 21. Pressure from bothperfusion line 1 and drainage line 2 may be monitored to determineintravenous pressure of the target organ. Target organ pressureinformation may be delivered to a pressure control unit in therapyisolation module 320, along with other appropriate physiologic signalsto control perfusion flow and drainage flow. Pressure control unit 325may act as a flow divider that is responsive to control signalsdelivered from sensors which sense pressure at, for example, theperfusion port, so as to adjust the division of drainage flow among theperfusion flow and the systemic flow. Sensors may be deployed to detectnot only intravenous pressure, but also a variety of characteristics,and to communicate signals representative of values of suchcharacteristics to pressure control device 325 of the blood conditioningapparatus. The sensors may be adapted to detect characteristics, such aspressure, temperature, flow rate, electrogram signal, enzymeconcentration, and therapeutic drug concentration.

Perfusion and drainage pumps 318, 324 may control flow rates, flowdirection, and timing to provide synchronized flow patterns to thevarious target tissue structures/organs. By receiving flow informationfrom perfusion line 1 and drainage line 2, pressure/flow control device325 is able to adjust deactivation therapy according to the volume ofexcess flow delivered to therapy deactivation module 330. Data onperfusion and excess flow volume may also be delivered to temperaturecontrol devices 316, 332 to optimize temperature adjustment of perfusateand systemic flow.

In some embodiments, temperature control device 316 receives temperatureinformation from a temperature sensor disposed in drainage line 2. Sucha temperature signal may be used as a feedback for localized therapeutichypothermia at the target tissue structure to monitor temperaturethereat. Moreover, confirmatory information regarding target tissuetemperature in a therapeutic hypothermia application may also beobtained by physiological signals, such as electrograms, including anelectrocardiogram from the myocardium. Temperature feedback informationmay be utilized to estimate therapy delivery or concentration in thetarget tissue structure. Such information may also be useful forlocalized therapy delivery for bioactive agents which are difficult toremotely sense. A further temperature control may include a systemic ortotal body temperature sensing, such that the excess flow may be used toregulate the body temperature, and to maintain a desired organ tosystemic temperature gradient. In such a manner, target organtemperature may be maintained within a therapeutic range, whilemaintaining a desired (e.g. normal) body temperature.

Example Applications

The following sets forth example clinical applications of the system ofthe present invention. The applications described herein are notintended to be limiting to the various applications contemplated by thepresent invention.

Isolated Organ-Specific Therapeutic Hypothermia

Therapeutic hypothermia is a treatment using mild hypothermia (32° C. to34° C.) to prevent or minimize reperfusion injury. The treatment hasshown to provide significant benefits for both ischemic and traumaticinjuries for many organs (e.g. heart, brain, liver, and kidney, etc.)The goal of using this isolated organ-specific therapy delivery is tolocalize the cooling therapy to a specific target organ, whilemaintaining normal body temperature. This will enable the use oftherapeutic hypothermia for conscious patients (i.e. withoutmedically-induced coma and strong muscle relaxant), and prevent systemicside effects of the cooling treatment.

Since the indication of use for therapeutic hypothermia is mostly foremergency circumstances, timely implementation and ease of use is animportant factor in the design of a therapy delivery device. Therefore,a system requiring only venous access is most preferred. Selectionbetween one-vein access and two-vein access techniques depends on thetarget organ. In applying therapeutic hypothermia to the heart, theone-vein access may be a better choice because of the coronary sinusbeing a major venous drainage of the ventricular muscle, and its easyaccess and well-established procedure. For application to the brain, thetwo (left and right) internal jugular veins make the two-vein accesstechnique a possible candidate. Nevertheless, the complete isolationorgan-circulation techniques described herein can also be used fortherapeutic hypothermia.

For the device setting of therapeutic hypothermia, there is not muchchange on the therapy delivery and isolation parts from the generaldescription. For solely cooling treatment, there is no need for theexternal supplemental unit. However, small amount of drugs (i.e. a betablocker to control heart rate and myocardial contractility,anti-arrhythmia or anti-convulsion drugs, and/or magnesium sulfate forboth heart attack and stroke) can also be administrated locally to thetarget organ with hypothermia treatment. The target organ may have theadditional benefit of increased oxygenation from the organ isolationtechnique as well. The only required component for the deactivation partis the systemic temperature control.

The function of the target organs (i.e. particularly for the heart—acutemyocardial infarction, and the brain—stroke) may be preserved while thelocalized delivery technique is employed. There are two major impacts ofthese novel localized delivery methods for standard heart attack andstroke treatment. One is organ cooling prior to reperfusion. For thefirst time, the heart or the brain or other target organs may be cooledto the therapeutic temperature in only a few minutes (typically within15 minutes). This allows for cooling before an establishment of thelocal reperfusion (balloon/stent or thrombolytic angioplasty), which isknown to provided the best cell protection. Secondly, extended coolingtreatment (e.g. 12 to 72 hours) is possible for awake patients. Thismaximizes the cell salvaging benefit of mild hypothermia. For cardiacarrest, a local brain cooling can be used without medically-inducedcoma. Therefore, a time period exceeding 24 hours of mild hypothermiacan be used. Neurological signs of cardiac-arrest patients' can bemonitored while the cooling treatment is being employed, which may beused to individually optimize the length of therapeutic hypothermia.

Isolated Organ-Specific Drug & Chemotherapy

Many drugs require a high therapeutic dosage at the target organ to beeffective, which cause severe systemic side effects. Chemotherapy is anexample of a highly toxic bioactive agent. Many cancer patients die fromcomplications of the chemotherapy rather than from the cancer. Thatlimits the use of chemotherapy for many patients. The isolated organtherapy delivery technique can also be used to deliver drugs thatrequire high organ-to-systemic concentration gradient. The goal is tomaintain the high concentration in the target organ, but keep a very lowconcentration in the systemic circulation. Chemotherapy is a goodcandidate for this localized therapy delivery, as its administrationusually takes several hours to few days. The organ isolation can also bemaintained for additional days thereafter.

Since this type of application is usually employed in scheduled visits,the choice of the organ isolation technique is more open and depends onthe target organ or organ segment or tumor vasculature. For example, atwo-vein access partial isolation technique may be an optimal choice forbrain. For the liver, however, both 2-vein and 1-vein access partialisolation techniques may be suitable, depending on the desired locationand extent of circulatory isolation within the liver. One-access partialorgan circulatory isolation may be a good candidate for the renal veinof the kidney. In addition, a complete isolation technique can also bevery useful if the risk of local and systemic arterial embolization canbe managed. For cancer masses, the eligibility or choices of theorgan-circulatory isolation technique purely depends on the vascularstructure.

Therapeutic agents may be added to the perfusion line to deliverlocalized therapy to the target organ. Although there may be no need foraltering organ temperature, a small warmed or cooled saline may beinjected in the perfusion line and the temperature sensing on thedrainage line may be able to calculate effectiveness of the therapydelivery. The feasibility of this technique depends on the vasculararchitecture of the target organ and the arrangement of the isolationtechnique.

If available, antidotes for drugs can be used to deactivate orneutralize the therapy delivery. Mini organ dialysis may also be used toexcrete some drugs or therapeutic agent from the blood volume returningto the systemic circulation. Nevertheless, localized delivery andisolation of the therapy alone without the deactivation may be able toraise the concentration of the therapeutic agents in or at the targetorgan to a sufficient extent, while contamination to the system may bediluted to a more tolerable level for the patients. Because of therelatively small volume of the target organ (compared to the totalbody), a relatively small amount of drugs are likely needed in alocalized therapy delivery approach, which also reduces treatment costsfor expensive drugs like chemotherapy. Since systemic side effects maybe minimized by the localized delivery method of the present invention,existing chemotherapy protocols may be revised for longer administrationperiods and higher dosages for the local organ.

Isolated Organ Protection

Conventional administration of toxic bioactive agent therapy is throughsystemic treatment. However, the therapeutic bioactive agent may havetoxicity to certain vital organs-such as liver, kidney, or heart. Inaddition to providing localized therapy delivery, the organ-circulatoryisolation technique of the present invention can also be used to protectthe target organ from a systemic treatment by creating a highsystemic-to-organ concentration gradient. Therefore, the organcirculation is isolated or separated from the system circulation.

In this application, complete organ-circulatory isolation may be themost effective, as it prevents or significantly reduces incoming bloodflow from the arterial system. Nevertheless, the partial isolationtechniques described herein are also useful in diluting and neutralizingthe toxicity from the incoming arterial flow. The vasculature of thetarget organ is the most dominant factor in selecting theorgan-circulatory isolation technique. For example, the presentlydescribed partial isolation technique may be a better choice for theliver, while the kidney may be a good candidate for either of thecomplete and partial isolation techniques.

To accommodate this application, the therapy deactivation module mayinstead be on the perfusion side, as shown in FIG. 22. However, theoxygenation and the temperature control units may remain on the(protective) therapy delivering module. The goal of this application isto deactivate or neutralize the therapy. In case of the need to protectboth kidneys with the complete isolation technique of the presentinvention, a temporary hemodialysis through flow-volume adjusting linemay be required as the kidney's dialysis function is shielded from thesystemic blood circulation.

Isolated Organ-Specific Cell-Based Therapy

Stem cell therapy or regenerative medicine is in development, and maysoon become a common therapy modality. One of the many challenges facingcell therapy is low cell seeding or survival rate. Cells aretraditionally delivered through an arterial line such that a majority ofdelivered cells pass through the capillary or collateral circulation tooquickly, and do not have enough time to seed into the tissue bed.Delivering these cells through the venous system may help increasecontact time with the tissue bed. Moreover, the organ-circulatoryisolation of the present invention may recycle cells to the targetorgan. Therefore, the organ isolation techniques can be used to improveseeding rate for cell-based therapy. Because of the smaller volume of anorgan (vs. the volume of the total body), a relatively smaller number ofcells may be needed to promote cell based therapy in the system of thepresent invention, as compared to conventional systemic administrations.

Partial organ-circulatory isolation techniques may be first consideredto avoid prolonged arterial access during the localized therapydelivery. The choice of one-vein access or two-vein access depends onvascular architecture of the target organ—in the same manner discussedin previous applications. The device setting may require a cellseparator to recycle cells back to the target organ, as shown in FIG.23. However this may not be a crucial component if the supply for thecell therapy is not too limited. This application may not need otherdeactivation components.

Examples of this application may include cell-based therapy for chronicmyocardial infarction, chronic liver failure, and chronic renal failure.Stem cells may be injected through these diseased organs to permanentlyreinstall the failed organ function. This can also be combined with mildcooling, shown FIG. 24, which has been shown to improve cell survivalrate.

Isolated Organ-Specific Plasma Paresis and Dialysis

In events of large organ injury where toxicity secondary to the injurycan cause a severe insult to the entire body, this organ isolationmethod can be used to separate the organ from the systemic circulationprior to performing plasma paresis and/or dialysis to remove thetoxicity produced by the injured cells. By doing so, localized treatmentcan also be employed to help cell recovery and also to protect the organfrom reperfusion injury. One example of this application is to isolatean extremity (i.e. arm or leg) in which the blood supply has been cutfor more than several hours. This is usually an indication foramputation to prevent reperfusion injury to the whole body that couldcause severe complications, such as acute renal failure or heartfailure, or even death. Another example application is gangrene of largeinternal organs.

Since this application is primarily for large volume organs, thecomplete organ isolation technique of the present invention may be anappropriate choice. For arms and legs, the vascular access for botharterial and venous systems is easily obtained through the brachial oraxial arteries and veins, and the femoral arteries and veins. The devicesetup may be as shown in FIG. 25, wherein the toxicity deactivation unitmay be adapted to treat the drainage flow. Oxygenation and mild coolingmay be included to provide tissue oxygen supply and to preventadditional reperfusion damage to injured tissue.

This itself is a treatment, rather than just a therapy delivery, thatcould help preserve arms or legs which otherwise would be amputated.This can help reduce disability which is extremely expensive not only tothe healthcare system but to the society as a whole—and more importantlyhelp improve or preserve patients' quality of life.

The invention claimed is:
 1. A system for delivering localized therapyto a tissue structure, said system comprising: a catheter apparatuscomprising: (i) a venous perfusion line adapted to deliver perfusate tothe tissue structure; (ii) a venous drainage line adapted to recoverdrainage flow from the tissue structure; and (iii) an occlusion deviceadapted to selectively substantially occlude venous blood flow betweenthe tissue structure and systemic blood circulation; a bloodconditioning apparatus associated with said venous catheter apparatusfor supplying perfusate to the tissue structure through said venousaccess line, and recovering the drainage flow from the tissue structurethrough said venous drainage line, said blood conditioning apparatusincluding a controller that is responsive to a signal from a sensordetecting one or more conditions of the tissue structure, the controllerdirecting said blood conditioning apparatus to deliver perfusate andrecover drainage flow based upon an adjustable time ratio algorithmusing the one or more tissue structure conditions as inputs to the timeratio algorithm.
 2. A system as in claim 1 wherein the one or moreconditions include systole and diastole of a heart.
 3. A system as inclaim 2 wherein said sensor detects a signal that is indicative of theonset of a systole or diastole.
 4. A system as in claim 3 wherein saidcontroller directs a perfusion valve to open or close to controlperfusate through said venous access line, and a drainage valve to openor close to control drainage flow through said venous drainage line, andwherein said time ratio algorithm is programmed to instruct saidcontroller to: (i) open or permit open said perfusion valve during oneor more consecutive diastole conditions; (ii) open or permit open saiddrainage valve during one or more consecutive systole conditions; and(iii) close or permit closed said perfusion valve during systoleconditions.
 5. A system as in claim 4 wherein said time ratio algorithmis programmed to instruct said controller to close or permit closed saiddrainage valve when said perfusion valve is open.
 6. A system as inclaim 4 wherein said time ratio algorithm is programmed to periodicallysimultaneously close or permit closed said perfusion valve and saiddrainage valve.
 7. A system as in claim 4 wherein said perfusion valveand said drainage valve are controlled closed or permitted closed whennot open.
 8. A system as in claim 4 wherein said time ratio algorithm isprogrammed to instruct said controller to simultaneously close saidperfusion and drainage valves.
 9. A system as in claim 1 wherein saidtime ratio algorithm is adjustable to change its programmed instructionsto said controller, based upon a factor selected from at least one of atemperature condition, a pressure condition, and an extent of controlledcirculation from the tissue structure temperature or pressure condition.10. A system as in claim 9 wherein the factor is measured at the tissuestructure.
 11. A system as in claim 1 wherein said blood conditioningapparatus includes a heat exchanger for temperature conditioning theperfusate.
 12. A system as in claim 11 wherein the perfusate includesautologous blood cooled to less than about 35° C.
 13. A method forlocalized therapy of a tissue structure, said method comprising: (a)providing a catheter apparatus having: (i) a venous perfusion line forconveying perfusate to the tissue structure; (ii) a venous drainage linefor recovering venous drainage flow from the tissue structure; (iii) asystemic access line having a systemic port; and (iv) an occlusiondevice; (b) providing a blood conditioning apparatus associated withsaid catheter apparatus for controlled perfusion and drainage to andfrom the tissue structure, said blood conditioning apparatus including:(i) a first sensor for sensing a condition of the tissue structure; (ii)a controller that is responsive to signals from said first sensor; (iii)a perfusion pump for delivering perfusate through said venous perfusionline; (c) positioning said catheter apparatus within a venous drainageoutlet of the tissue structure; (d) actuating said occlusion device tosubstantially occlude venous drainage from the tissue structure; (e)pumping the perfusate through said perfusion line with said perfusionpump, wherein the perfusate is conditioned prior to delivery to thetissue structure; and (f) controlling flow through said perfusion lineand said venous drainage line in accordance with an adjustable timeratio algorithm that uses as an input the sensed tissue structurecondition.
 14. A method as in claim 13 wherein said first sensor detectsa signal that is indicative of the onset of a tissue structure cycle,said tissue structure cycle including systole and diastole of a heart.15. A method as in claim 13 wherein said first sensor is anelectrocardiogram.
 16. A method as in claim 13, wherein conditioning theperfusate includes cooling the perfusate to less than about 35° C.
 17. Amethod as in claim 16, including generating at least a portion of theperfusate with the venous drainage flow.
 18. A method as in claim 17,including generating systemic flow by conditioning the venous drainageflow, and controllably dispensing the systemic flow to venous systemiccirculation through said systemic port.